Drug Device Electroporation System

ABSTRACT

Active Energy Facilitated Drug Delivery platform for delivering therapeutics to biological tissue through electrical conductivity. This delivery method is comprised of an elastic alloy to encase a balloon or drug deposition, where the alloy acts to emit an electric field in aiding and actively allowing the pharmaceutical agent to have enhanced permeation, binding and internalization to cells and the biological matrix. A therapeutic agent is deposited onto a balloon to embody the drug deposition, reservoir whereby the electrical field facilitates the active transfer of a pharmaceutical agent to the target tissue is described.

BACKGROUND

The narrowing of the blood vessels is commonly referred to as stenosis or restenosis that can occur after injury to the vessel wall, in example atherosclerotic injury, calcified plaque injury, or revascularization. Surgical procedures such as angioplasty, vascular grafting and transplantation can result in inflammation and/or overcompensation of tissue and result in restenosis. Percutaneous trans-luminal vascular intervention by either angioplasty balloons, atherectomy devices or stents is a frequent cause for restenosis.

Restenosis is mediated by overgrowth of vascular smooth muscle cells and the many smooth muscle cell intermediates as well as fibroblasts and other structural support cells and material in response to injury. This overgrowth is commonly referred to as hyperplasia or excessive neo-intimal growth occluding, or obstructing the flow of blood through the blood vessel. This type of vascular disease gives rise to clinical indications involving organ dysfunctions such as hypertension, cardiac failure, limb loss and chronic pain. Much effort has been made to overcome vascular disease without causing harmful secondary effects from potential and existing treatments.

New therapeutic modalities are needed to avoid unwanted long term complications of standard percutaneous therapies. The current invention has the potential to bypass these shortcomings by efficiently delivering therapeutic agents to the artery without resorting to procedures that result in acute tissue damage or chronic irritation.

Drug Coated Balloons (DCB)s were developed in an effort to outperform stenting with the use of anti-stenosis drugs. Cell senescence drugs are used to coat angioplasty balloons and are inflated to deliver drug to localized stenosis lesions in the artery. The senescence of cells at the site of angioplasty presumably prevents neo-intimal growth while allowing the endothelium to return, thereby shielding the smooth muscles from contents in the blood stream that cause inflammation and scar tissue growth. DCBs are still ineffective in the ability to distribute drugs in efficacious concentrations and/or evenly within vessel wall in some anatomical locations. In addition, clinical overexpansion of DCBs are useful to drive the drug into the tissue, but this also causes tissue trauma which can promote a vessel diameter late loss, which is particularly harmful to small vessels, such as the coronaries or leg arteries below the knee.

In the current invention, using an added electrical component known as electroporation to a DCB to enhance the drug binding efficiency to its target is the principal method for overcoming the problems of both DCBs and stents. Electroporation is a method commonly used in Cell Biology as a method of introducing a foreign material (i.e. DNA, virus, chemical compounds, etc. . . . ) into the intercellular or cytosol space. The mode of electroporation operates by sending an electrical or high voltage, low current electromagnetic pulse across the membrane of the cells or tissue whereby momentarily destabilizing the cellular matrix/membrane and exposing both inter and intracellular channels to any molecules that would otherwise require active transport into the cell or matrix.

BRIEF DESCRIPTION OF FIG. AND IMAGES

FIG. 1a : Illustration of the overall structure of a balloon and cage. The objects labeled +/− (cathode/anode) are made from any conducting fiber or material thereof (i.e. Copper, Tungsten, Aluminum, carbon based etc. . . . ) for delivering electrical currents by pulsation across the membrane.

FIG. 1b : The detailed view of the proximal region of the balloon. The conductive braided fiber from the shaft continues to the cage assembly over the balloon. This assembly will be secured to the balloon surface material such that when inflated the balloon and cage will contact the tissue. The polarity can be placed in alternating orientations and is only a representation of the closed circuit formation.

FIG. 1c : Shown is the cross section of the balloon catheter shaft where the electrical conducting material is included in the extrusion process of the material. The “Guide-wire Lumen” is the hollow space that allows the vascular intervention wire to pass.

FIG. 1d : Representative image showing exploded view of the hub connection and electrode lead. This illustration is a detailed view of the proximal end of the device or hub connector end of the catheter. The aggregation of the braid fibers will act as an electrical conductor to transfer electric pulses to the intended target.

FIG. 1e : Representative drawing of the device with electrical conducting paddles as mentioned in the device description section.

FIG. 1f : FIG. 5: A cross section illustration of the angioplasty balloon at the cathode plate.

FIG. 1 g. Representative illustration of the device and the composition of parts where an alternative configuration of elastic conducting cage is expanded with the balloon expansion as described in Claim 1. The balloon is encased by the cage and shown in this FIG. with connections to the conducting element comprising the catheter body. This drawing of the device illustrates the angioplasty balloon in the inflated form with the cage expanded the balloon. The catheter body is braided with an electrical conducting material from catheter hub to balloon body. Electrical conducting braids are continues to the wire electrical connection on the hub end and extended to braid connections integrated into the cage.

FIG. 2: This photograph shows the setup of the closed loop circulation system as mentioned in this document to mimic the arterial blood flow exposed to test articles and artery. Closed loop fluid circulation system comprising isotonic media for tissue flow and experimentation. Tissue is inserted into the chamber and attached by canulas and allowed media flow through provided by the peristaltic pump. Device in implanted and deployed with or without electric field.

FIG. 3: Proof of concept data illustrating a comparison between the same device in use with and without electric field.

FIG. 4. A representative analysis is shown here where the results for the samples of interest are shown in the left panel as compared to the standard curve in the right panel.

FIG. 5: First prototype with the ReeKross Balloon acquired from ClearStream Bard

FIG. 6: Second prototype with a commercially available TriReme Chocolate device

FIG. 7: Gene Pulser II, the energy source acquired and used for delivering energy to transfer PTX onto and into the target tissue

FIG. 8: This is a photograph of the tissue connected to the closed circuit with media flowing through it.

FIG. 9. Shown in this FIG. are photographs describing how the tissue is opened to expose the lumen to the solvent extraction

BRIEF SUMMARY

In accordance with the purposes of the disclosed materials, compounds, compositions, and methods, as embodied and broadly described herein, the disclosed subject matter, in one aspect, relates to compounds and compositions and methods for preparing and using such compounds and compositions. In another aspect, disclosed herein is the use of pharmaceuticals in combination with a modified angioplasty device that will aid the drug delivery into the target location with an electrical pulse commonly known as electroporation.

The advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. 

1. A balloon catheter In which the balloon is messed within an elastic conducting alloy cage, wherein the cage is bonded at both distal and proximal balloon ends with an electrical connection at the proximal taper to conductive elements along the body of the catheter to a proximal connection to an electrical power source, and wherein the working length of the balloon and optionally the cage section are coated with materials comprising a therapeutic bio-active agent and optional excipients.
 2. The device of claim 1 in which the elastic conducting alloy is nitinol.
 3. The device of claim 1 whereby the electrical conducting field can be provided by en energy generator where one polarity is delivered to the emitter while the opposing polarity is grounded to the surface or body of the Intended target.
 4. The device of claim 2 whereby the energy field is primarily voltage driven with low current.
 5. The device of claim 1 whereby the power supply delivers a square wave with a voltage range of 0.001 kV to 5 kV.
 6. The device of claim in which the bio-active agents will comprise the broad classes of anti-neoplastic agents, mTOR inhibitors, taxanes, neurotoxins, steroids, and non-steroidal anti-inflammatory agents.
 7. The device of claim 4, wherein the coating is also comprised of one or more of an organic excipient such as a polymer or oligomer with hydrophilic character (e.g. PEG), a citrate ester, an adipate ester, urea or substituted urea, a surfactant such as sorbitan mono oleate or block co-polymers of PEO and PPO.
 8. The device of claim 1, wherein the conductive elements along the catheter body are shielded by dielectric material(s) so that the conductive energy is delivered to the emitter end in compliment with the pharmaceutical agent.
 9. The device of claim 1, wherein energy emission can be delivered through any exposed conductive material with leads connected to the energy generator whereby anode and cathode can be bridged to form an energy field.
 10. The device of claim 7 whereby a coating with a therapeutic as described in claims 2,4,5 is used in conjunction.
 11. A method of treating stenosis or preventing restenosis using a balloon catheter in which the balloon is incased within an elastic conducting alloy cage, wherein the cage is bonded at both distal and proximal balloon ends with an electrical connection at the proximal taper to conductive elements along the body of the catheter to a proximal connection to an electrical power source, and wherein the working length of the balloon and optionally the cage section are coated with materials comprising a therapeutic bio-active agent and optional excipients, and wherein an electric power source is applied to the device while the balloon is inflated in the treatment zone.
 12. The method of claim 9, comprising the composition in combination with a method for drug delivery by electro-poration, electromechanical or electric pulse for enhancing pharmaceutical or genetic material uptake and transfer.
 13. The method of claim 10, wherein the subject is undergoing or has undergone a vascular procedure.
 14. The method of claim 10, wherein the vascular procedure comprises balloon angioplasty.
 15. The method of claim 10, wherein the vascular procedure comprises vascular stenting.
 16. The method of claim 10, wherein the vascular procedure comprises revascularisation.
 17. The method of claim 10, wherein the vascular procedure comprises arterial by-pass graft.
 18. The method of claim 10, wherein, the vascular procedure comprises a Percutaneous Transluminal Vascular intervention (PTVI).
 19. The method of claim 10, wherein the vascular procedure comprises intravascular device implantation.
 20. The method of claim 10, wherein the vascular procedure comprises arterial denervation.
 21. The method of claim 10, further comprising determining the degree of restenosis, arterial hyperplasia after administering the composition.
 22. The method of claim 10, comprising the composition in combination with implantable devices.
 23. The method of claim 10, comprising the composition In combination with particulate capture devices. 